HPV Vaccine Protects Against Cervical Cancer Precursors

Action Points

Explain that the human papillomavirus (HPV) vaccine offered excellent protection against the precursors (CIN2 and CIN3) of invasive cervical cancer, plus partial protection against four other nonvaccine oncogenic HPV types.

Note that an important finding of the first study was the high efficacy of the bivalent HPV vaccine (Cervarix) particularly among adolescent girls not yet sexually active.

The human papillomavirus (HPV) vaccine offered excellent protection against the precursors (CIN2 and CIN3) of invasive cervical cancer, plus partial protection against four other nonvaccine oncogenic HPV types, according to two studies.

An important finding of the first study was the high efficacy of the bivalent HPV vaccine (Cervarix) particularly among adolescent girls not yet sexually active. These results, published in The Lancet Oncology, suggest the importance of modifying screening programs to target early adolescents, said Matti Lehtinen, PhD, of the University of Tampere in Finland.

The four-year end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults) showed excellent efficacy against CIN3+ and adenocarcinoma in situ irrespective of HPV DNA in the lesion. The trial included almost 19,000 healthy women ages 15 to 25, who were HPV-naive at baseline, with no more than six lifetime sexual partners.

The women -- who were from 14 countries in the Asia-Pacific region, Europe, Latin America, and North America -- were randomly assigned to receive the HPV-16/18 vaccine, which targets about 70% of cervical cancers, or a control (hepatitis A vaccine).

Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85.5 to 100) in the total vaccinated cohort of women with no evidence of infection (TVC-naive) and 45.7% (CI 22.9 to 62.2) in the total vaccinated cohort group (TVC).

Vaccine efficacy against all CIN3+ (irrespective of HPV type and including lesions with no HPV DNA detected) was 93.2% (CI 78.9 to 98.7) in young women not infected with HPV (TVC-naive) versus 45.6% (CI 28.8 to 58.7) in the total vaccinated cohort (TVC group). In the TVC-naive women, vaccine efficacy against all CIN3+ was higher than 90% in all age groups.

In the previously unexposed women (TVC), vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15 to 17 age group, and decreased progressively in the 18 to 20 and 21 to 25 age groups. Vaccine efficacy against all adenocarcinoma in situ was 100% in the never-infected group and 76.9% in the total vaccinated cohort (TVC).

Serious adverse events occurred in 835 (9%) and 829 (8.9%) of women in the vaccine and control groups, respectively. Only ten events (0.1%) and five events (0.1%), respectively, were considered to be related to vaccination.

Study limitations included the fact that the distribution of women from various countries across the different cohorts may weaken the study's generalizability. Also, the exclusion of women with more than six lifetime sexual partners lessened generalizability, especially in the 21 to 25 year age group in the TVC, where some of the excluded women most likely had multiple infections.

Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of young adolescents before their sexual debut will probably achieve maximum benefits, Dr. Lehtinen wrote. The researchers also noted substantial vaccine efficacy in a population approximating the general population of sexually active women, suggesting that catch-up vaccination would provide some benefit.

In a second Lancet Oncology study analyzing results from the PATRICIA trial, Cosette Wheeler, PhD, of the University of New Mexico in Albuquerque, and colleagues reported that the bivalent HPV vaccine showed cross-protection efficacy against four oncogenic nonvaccine HPV types in different trial cohorts representing diverse groups of women:

HPV-33

HPV-31

HPV-45

HPV-51

These four types, plus HP-16/18, cause about 85% of cervical cancer they said. Furthermore, there is a particularly high risk of HPV-33 infection progressing to cervical lesions, while HPV-45 is over-represented in adenocarcinoma.

Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 coinfection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51, the researchers reported

In the most conservative analysis of vaccine efficacy against CIN2+, where all cases coinfected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in two other groups: ATP-E (no evidence of infection at the outset with the HPV type under analysis) and TVC-naive (uninfected at the outset).

Vaccine efficacy against CIN2+ was associated with the composite of 12 nonvaccine HPV types, with or without HPV-16/18 coinfection, at 46.8% in the ATP-E group, 56.2% in the TVC-naive group, and 34.2% in the TVC group. Corresponding values for CIN3+ were 73.8% in ATP-E group, 91.4% in the TVC-naive group, and 47.5% in the TVC group.

Overall, Wheeler said, these findings suggest that the the cross-protective efficacy of the vaccine when given to HPV-naive women might provide additional protection against cervical cancer but long-term follow-up is needed.

In an accompanying commentary, Mark Schiffman, PhD, and Sholom Wacholder, PhD, of the National Cancer Institute in Bethesda, Md., wrote that increasing coverage, particularly of sexually-naive adolescent females, is the most important public health issue in HPV vaccine efforts. Nonetheless, they said, despite vaccine efficacy near 100% in HPV-naive women, the efficacy in the total vaccinated group decreased steeply with increasing age.

They also expressed concern about low vaccination rates in areas where cervical cancer and mortality rates are high; where alternative prevention is inadequate; and where current vaccines are too expensive and often difficult to deliver.

The long-term proof of the safety of HPV vaccine is a public-health priority. Use will increase as public trust in safety increases, they concluded.

The Lehtinen study was funded by GlaxoSmithKline, the makers of Cervarix.

All investigators at clinical sites, including Lehtinen, were funded through their institutions.

Many of the researchers are employees of GlaxoSmithKline Biologicals; G. Dubin holds a relevant patent. Other firms contributing to the study include Merck Sharpe & Dohme, and Roche Molecular Systems.

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